Mercury salts of nitrogen heterocyclics and preparation thereof



3,041,335 MERCURY SALTS F NITROGEN EETERO- CYCLICS AND PREPARATEGNTHEREOF Max Hotter, Nntley, Ni, assignor to Hofimannlia Roche inc,Nntley, N..l., a corporation of New Jersey N0 Drawing. Originalapplication Apr. 21, 195?, Ser. No. 807,769, new Patent No. 2,949,451,dated Aug. 16, 1960. Divided and this application Get. 23, 1959, Ser.No. 848,217

11 Claims. (Ql. 260-242) This invention relates to novel chemicalprocesses and to novel intermediates therefor. More particularly, itrelates to the preparation of 2'-deoXy-5-fluorouridine and thymidine,the fi-anomers of which are known compounds. The invention relatesfurther to new chemical compounds useful as intermediates in thepreparation of 2-deoxy-S- fluorouridine and thymidine by the processesherein disclosed.

A comprehensive survey of various aspects of the invention may be had byreference to the following flow sheet, wherein the symbol Z represents amember selected from the group consisting of fluorine and methyl, andthe symbol R represents an 'aryl radical. Preferably, R represents aradical containing not more than ten carbon atoms selected from thegroup consisting of monocyclic aryl hydrocarbon radicals and negativelysubstituted monocyclic =aryl hydrocarbon radicals. Especially preferredare those embodiments of the invention wherein R represents an arylradical containing not more than ten carbon atoms se ected from thegroup consisting of phenyl, lower alkyl-phenyl (eg. p-tolyl, o-tolyl,p-ethyl-phenyl, xylyl, etc.), lower alkoxy-phenyl (e.g, anisyl,o-methoxy-phenyl, etc.), and halophenyl (e.g. p-chlorophenyl,o-chlorophenyl, p-bromophenyl, etc.) and nitrophe-nyl (e.g.pnitrophenyl).

FLOW SHEET 3,@ l,335 Patented June 26, 1962 On reference to the flowsheet, it will be seen that one important embodiment of the inventionrelates to a process of making 2'-deoxy-5-fiuorouridine which comprisesreacting 3,5diaroyl-Z-deoxy-Driboturanosyl halide withmono(5-fiuorouracilyl)mercury, thereby forming 1-(3,5-diaroyl-2'-deoxy-D-ribofnranosyl)5-fluorouracil, and hydrolyzing thelatter. 7

Another important embodiment of the invention relates to a process ofmaking thymidine which comprises reacting3,5=diaroyl-2-deoxy-1Dribofuranosyl halide with monothyminylmercury,thereby forming 1-(3,5-diaroyl- 2'- deoxy-D-ribofuranosyl)thymine, andhydrolyzing the latter.

The compounds of Formula IV above are also novel, and these tooconstitute important embodiments of the invention. Species of CompoundIV may be prepared via several novel processes and intermediates, andthese constitute subsidiary aspects of the embodiments of the inventionhere under discussion. Thus, in one aspect, the invention provides aprocess of making mono(5- fluorouracilyDmercury which comprises heatingan alcoholic solution containing, dissolved therein, bisQl-acetyl-5-fluorouracily1)mercury, a mercuric salt of an organic carboxylic acidand a lower alkanol. The invention also includes the novel compoundbis(1-acetyl-5-fluorouracilyDmercury. In another aspect, the inventionprovides a process of making mono(S-fluorounacilyDmercury whichcomprises heating a solution containing, dissolved therein,l-acetyl-S-fluorouracil and a mercuric salt of an organic carboxylicacid. The invention also includes the novel compoundl-acetyl-S-fluorouracil. In still another aspect, the invention providesa process of making mono- (S-fluorouracilyDmeroury which comprisesheating a solu tion containing, dissolved therein, S-fluorouracil and amercuric salt of an organic carboxylic acid. In still an other aspect,the invention provides a process of making monothyminylmercury whichcomprises heating a solution containing, dissolved therein,l-acetylthymine and a mercuric salt of an organic carboxylic acid. Theinven- I vention also includes tautomeric forms wherein carbonyl groupsare present, in whole or in part, in enolized condition. Moreover,Whereas the mercuric salts of organic carboxylic acids referred to aboveinclude such compounds as mercuric formate, mercuric acetate, mercuricbenzoate and the like, it is preferred to employ mercuric acetate.

With reference again to the flow sheet, and considering in greaterdetail the various steps or stages of the processes of the inventiondisclosed in the flow sheet:

The stage I- II) comprises the acetylation of S-fluorouracil or ofthymine. This can be accomplished by direct reaction of theS-substituted pyrimidine with an acetylating agent, in an inert solventmedium if desired. A convenient method comprises refluxingS-fluorouracil or thymine with acetic anhydride in the present of asmall amount of a tertiary organic base, e.g. pyridine.

The stage (II- 111) comprises conversion of l-acetyl-S- fiuorouracil tobis(l-acetyl-S-fluotouracilyl) mercury. This can be accomplished byliquid phase reaction of dissolved l-acetyl-S-fluorouracil with adissolved mercuric salt of an organic carboxylic acid (preferablymercuric acetate), in the proportion of substantially one mol ofacetylfluorouracil to 0.5 mol of mercuric salt. A convenient methodcomprises dissolving 1-acetyl-5-flnorouraoil in a lower alkanol byheating, and mixing the warm solution with a half-molar proportion ofmercuric acetate.

The stage (Il1 IV) comprises refluxing bis(1-acetyl-5-fluorouracilyl)mercury in a lower alkanol with a mercuric salt of anorganic carboxylic acid (preferably mercuric acetate), in proportions ofone mol of his compound to at least one mol of mercuric salt, preferablyin a proportion of substantially one mol to one mol. A reaction takesplace in which the acetyl group is removed by alcoholysis andsimultaneously replaced by mercury.

As indicated in the flow sheet, alternative procedures are alsoavailable for making mono(5-fiuorouracilyl)mercury.

Thus, one form of the process (II- IV) comprises direct formation ofmono(5-fluorouracilyl)mercury from l-acetyl-S-fluorouracil. This can beaccomplished by reacting the latter with a solution of a mercuric saltof an organic carboxylic acid (preferably mercuric acetate) in a loweralkanol; in a proportion of one mol of acetylfluorouracil to more than0.5 mol'of mercuric salt, preferably in a proportion .of substantiallyone mol to one mol.

Another form of the process (Il IV) comprises formation ofmonothyminylmercury from l-acetylthymine. This can be accomplished byreacting 'l-acetylthymine with a solution of a mercuric salt of anorganic carboxylic acid (preferably mercuric acetate) in a loweralkanol, in the same manner described above for mono(5-fluoroura.-cilyl)mercury. It is preferred to use the pyrimidine reactant and themercurating reagent insubstantially equimolar proportions. v

A direct procedure for preparing mono(5-fluorouracilyl)mercury fromS-fluorouracil (=I IV) comprises reacting dissolved 5-fluorouracil witha dissolved mercuric salt ofgan organic carboxylic acid (preferablymercuric acetate). Thus, S-fiuorouracil can be reacted with mercuricacetate in solution in hot water or dioxan. 'A preferred methodcomprises mixing a hot methanolic solution of mercuric acetate with ahot aqueous solutionof 5-fiuorouracil; a

I The novel condensation step of the invention (IV-l-V-eVI) is effectedby heating a mixture of the two reactants in an inert organic liquid. Aconvenient mode of execution comprises adding3,5-diaroyl-2-deoxy-D-ribofuranosyl chloride to a suspension ofmono(5-fiuorouracilyl)mercury or monothminylmercury in toluene andrefluxing the material, then adding potassium iodide to the mixture inorder to remove mercuric chloride from the toluene layer, andprecipitating the condensation product by addition of heptane to thetoluene layer, or by concentrating the toluene layer. The crystallinereaction product obtained is usually a'mixture of anomeric forms. Themixture can be subjected to the next step of saponification withoutseparation of the anomeric forms, if desired. Alternatively, the twoanomers can be separated by fractional crystallization, and theseparated isomers can be individually saponified. p

The final step shown in the flow sheet, hydrolysis of (VI) to' (VII),can be accomplished by saponification methods known per se. For example,the aroyl groups can be removed by treating compound (VI) with anhydrousammonia in ethanol. A preferred embodiment of this aspect of theinvention as it relates to the preparation of 2'-deoxy-5-fluoronridinecomprises treating1-(3,5-diaroyl-Z-deoxy-D-ribofuranosyl)-5-fluorouracil with methanolicbarium methylate.

This application is a division of my copending applica tion Serial No.807,769, filed April 21, 1959, now U.S. Patent No. 2,949,451, which inturn is a continuation-inpart of my copending application Serial No.787,118, filed January 16, 1959, now abandoned.

The invention is further disclosed in the following examples, which areillustrative but not militative thereof. Temperatures are stated indegrees centigrade, uncorrected. The yields stated are also merelyillustrative.

EXAMPLE 1 1-Acetyl-5-Flu0r0uracil [IL Z=fluorinel 13.0 g. ofS-fluorouracil was refluxed, while stirring, with ml. of aceticanhydride and 0.5 ml. of pyridine until all had dissolved (10-15minutes). Refluxing was continued for 15 minutes longer. The clear,slightly pink solution was evaporated in a vacuum and the crystallineresidue was dissolved in m1. of hot toluene. The solution was separatedfrom a little insoluble, discolored, sandy material by filtering whilehot, with suction, and the liltrate was allowed to cool. The crystalswhich separated were filtered with such and dried at 70. The yield of 1acetyl-S-fluorouracil amounted to 14.9 g., corresponding to 86.5% oftheory; M.P. 128-129. Repeated crystallization from toluene did notchange the melting point. The compound was very rapidly saponified byalkali.

Analysis.C H N O F, calcd.: C, 41.7; H, 2.9; N, 16.3. Found: C, 4195; H,3.15; N, 16.07.

EXAMPLE 2 Bis(1,A cetyl-S-Fluorouracilyl) Mercury [TIL Z=flnorine1 5.1g. (0.03 mol) of l-acetyl-S-fluorouracil was dissolved in 50 ml. ofethanol at 75-78 and 5 g. of mercuric acetate was added While stirring.The organic mercury compound produced by the reaction precipitatedrapidly in the form of voluminous needle aggregates. After allowing themixture to cool and stand overnight, the product was filtered bysuction, washed with alcohol and dried at 70. The yield, 7.9 g., of his(l-acetyl-S-fluorouracilyD- mercury, corresponded to 97.5% of theory. Theamount of acetic acid found in the filtrate by titration was 1.80 g.,corresponding to 100% of theory.

'Bis(1-acety1-5-fluorouracilyl)mercury was a crystalline white fluifypowder melting with decomposition at 207. It was insoluble inconventional solvents, rather stable toward acetic acid, but not towardhydrochloric acid or alkali.

Analysis.(C H N O F) Hg, calcd.: N, 10.3. Found: N, 10.07, 10.24.

(a) From bis(1-acetyZ-S-fluorouracilyl)mercury.--5.4 g. (0.01 mol) ofbis(l-acetyl-S-fluorouracily1)mercury was added to a boiling solution of3.18 g. (0.01 mol) of mercuric acetate in 60 ml. of methanol. Themixture was refluxed for 20 minutes while stirring, allowed to cool, andthe solid was filtered by suction. The yield (6.6 g.) ofmono(5-fluorouracilyl)mercury corresponded to substantially 100%. Theproduct did not melt below 300. In the filtrate, about 0.02 mol ofacetic acid and 0.02 mol of methyl acetate were determined byalkalimetric titration.

(b) From 1-acetyl-5-flu0rouracil.-9.46 g. (0.03 mol) of mercuric acetatewas dissolved in 180 ml. of boiling methanol. After allowing thesolution to cool to 5560, 5.1 g. (0.03 mol) of l-acetyl-S-fluorouracilwas added in a single portion while stirring. After about one minute,mono(S-fiuorouracilyDmercury precipitated suddenly. The mixture wasallowed to stand overnight, and then the product was filtered bysuction, washed with methanol and ether, and dried first at roomtemperature, then at 70. The yield (9.9 g.) was practicallyquantitative.

(c) From 5-fluorouracil.-31.9 g. (0.1 mol) of mercuric acetate wasdissolved in 600 ml. of methanol while stirring and refluxing. A hotsolution of 13 g. (0.1 mol) of S-fluorouracil in 250 ml. of Water wasadded, causing an immediate precipitation of mono(5-fluorouracilyl)-mercury. The mixture was allowed to cool to room temperature whilestirring, and then was stirred for 12 hours longer. The fine precipitatewas filtered by suction. The filter cake, without being dried, wassuspended in 500 ml. of toluene and the mixture was stirred and heateduntil all methanol and water had distilled otf (drying by azeotropicdistillation). Toluene that distilled off with methanol and Water wasreplaced from time to time by fresh toluene. After allowing the mixtureto cool, the solid was filtered by suction and dried at 70 untiltoluene-free. The yield (33 g.) was quantitative.

Analysis.C.;HO N HgF, calcd.: N, 8.54. Found: N, 8.02.

6.6 g. of mono(5-fluorouracilyl)mercury, finely powdered, was suspendedin 300 ml. of toluene in a threeneck, round-bottom flask equipped withstirrer, moisturetrap and reflux condenser. The mixture was heated whilestirring and 100 ml. of toluene was distilled ofi (by discharging themoisture-trap when it had filled). The mixture then was refluxed for 20minutes longer without discharging the rnoisture-trap. 15 g. of3,5-di(p-toluoyl)- 2-deoxy-D-ribofuranosyl chloride (V, R=p-tolyl) wasadded. All of the material dissolved immediately to a substantiallyclear solution. Heating was continued for minutes and 50 ml. of toluene,accumulated in the moisture-trap, was taken off. The solution wasallowed to cool, and a solution of 20 g. of potassium iodide in 80 ml.of water was added to remove mercuric chloride from the toluene layer.The toluene layer Was separated, and to it was added 200 ml. of heptane,while stirring. The white crystalline deposit that rapidly developed wasfiltered by suction, washed on the filter with heptane and water, anddried at 70. The yield of 6.5 to 6.8 g. corresponded to 68-70% oftheory. The melting point of this mixture of isomeric forms of3',5-di(p-toluoyl)- 2-deoxy-5-fluorouridine was 195200.

The reactant 3,5-di(p-toluoyl)-2-deoxy-D-ribofuranosyl chloride,referred to above, can be made by the following procedure:

13.6 g. of 2-deoXy-D-ribose was dissolved in 245 ml. of methanol and 27ml. of a 1% solution of anhydrous hydrogen chloride in methanol wasadded. The mixture was allowed to stand for 20 minutes at 27 and thenwas stirred with 5 g. of silver carbonate until it no longer reactedacidic. The silver salts were removed by filtration with suction andwere Washed with methanol. The combined filtrate and washings wereevaporated in a vacuum as far as possible, 20 ml. pyridine was added andthe solution was again evaporated in a vacuum in order to remove thelast traces of methanol.

The syrupy residue of 1-methyl-2-deoxy-D-ribofuranoside was thendissolved in ml. of dry pyridine, the solution was cooled toapproximately 0, and 34 g. of p-toluoyl chloride was added in portionswhile maintaining the temperature below 20. After the addition of thechloride, the temperature was allowed to rise to 40-45 and kept therefor two hours. The mixture was diluted with 500 ml. of water, the oilyprecipitate was shaken out with 200 ml. of ether, the ether layer waswashed successively with water, KHSO, solution, water, KHCO solution,and water again, and was then dried over anhydrous sodium sulfate. Theether was removed by evaporation in a vacuum and the remaining syrup of3,5- di(p-toluoyl)-1-methyl-2-dexoy-D-ribofuranoside was dissolved in 20ml. of acetic acid while warming. The solution was cooled to below 10,and 80 ml. of a saturated solution of anhydrous hydrogen chloride inacetic acid was added at 0-l0. Anhydrous hydrogen chloride was conductedinto the solution for a few minutes, whereupon the product crystallizedrapidly, filling the whole vessel. After 10 minutes, the crystals werefiltered by suction. The filter cake was slurried with ml. of ice-coldabsolute ether, the slurry was filtered with suction, and the filtercake was rapidly transferred into a vacuum desiccator and dried in avacuum over soda lime at room temperature. The yield of3,5-di(p-toluoyl)-2-deoXy-D-ribofuranosyl chloride amounted to 27.5 g.

EXAMPLE 5 B-3',5-Di (p-Toluoyl -2-D e0xy-5-Fluor0idine [VI, Z:flu0rine,Rzp-tolyl] 20 g. of the mixture of isomeric forms of3',5-di(ptoluoyl)-2-deoxy-5-fiuorouridine, i.e. the combined yield ofthree batches made according to Example 4, were slurried with 60 ml. ofpyridine and the mixture was stirred till all lumps had dispersed. After30 minutes the crystalline mush was filtered by suction. The filter cakewas pressed free of mother liquor and Was washed with 10 ml. of pyridineon the filter. The pyridine was finally washed out with ether and thematerial was dried, first at room temperature, then at 70, to constantweight. Yield: 9.6 g., M.P. 220224. After one recrystallization from 100ml. of acetic acid, the yield amounted to 23-85 g. and the materialshowed a melting point of 229. The rotation (x was -17 (2% in pyridine).This anomeric form of 3',5'-di(p-t0luoyl)-2'-deoxy-5-fluorouridine isherein designated the fi-form.

20 g. of 5-3',5-di(p-toluoyl)-2-deoxy-5-fluorouridine was suspended in300 ml. of methanol and a small amount of alcoholic phenolphthaleinsolution (0.5-1 ml., 1%) was added. The suspension was cooled in iceWater, and a 0.43 N methanolic barium methylate solution was added todefinite alkalinity (40 ml.). The mixture was kept at 5-10, withoccasional shaking, till free of color. The above 0.43 N bariummethylate solution was added in 10 ml. portions while cooling in icewater until, after six hours, the alkalinity persisted and the suspendedmaterial had gone into solution. Altogether, 80 ml. of 0.43 N bariummethylate solution had to be added. The reacaosnsss 7 tion mixture wasallowed to stand in the refrigerator overnight (15 hours). Then 1 Naqueous sulfuric acid solution was added in an amount exactly equivalentto the barium methylate used. The colloidal precipitate of bariumsulfate could not be filtered. The mixture was, therefore, evaporated invacuo to a syrup, 200 ml. of acetone was added, the barium sulfate wasfiltered by suction through Celite and the filter residue was washedwith 100 ml. of hot acetone. The combined filtrate and washings wereevaporated in a vacuum, the residue was seeded and was washed with etherto remove methyl toluate. The ether-insoluble material crystallizedcompletely. It was collected by filtration and washed with ether. Theyield, 9.6 g. of [3-2'-deoxy-S-fluorouridine,

melting at 143, corresponded to 94% of theory. Recrystallization frombutylacetate gave 9.2 g. (90%) of material melting at 145.

EXAMPLE 7 a-3',5'-Di(p-T0luoyl)-2-Deoxy-5-Fluorouridine [V1, Zztluorlne,R=p-toly1l The first (pyridine) filtrate from Example was diluted with70 ml. of water and was allowed to stand. After one to two hours, morewater was added (70 ml.), and the crystals were filtered by suction.They were washed on the filter with water, a little alcohol and ether.Yield of dry material, 8.6 g., M.P. 205-210". This material wasdissolved in 258 ml. of boiling acetone and the solution was allowed tocrrystallize for 48 hours in a refrigerator. The crystals were filteredby suction (5.8 g. of a-anomer, M.P. 212-2l3), and the mother liquor wasevaporated to dryness. The crystalline residue from the mother liquorwas washed with ether and collected by filtration (2.6 g. of mixed uandB-anomers, M.P. 195-200). This mixture was again treated for separationof the isomers, by slurrying the mixture with 7.8 ml.

of pyridine for 30 minutes, whereupon another crop of fi-anomer (0.8-1g.) was obtained.

The a-anomer, melting-at 212-213", was recrystallized from five timesits weight of glacial acetic acid. The purifiedu-3',5-di(p-toluoyl)-2'-deoxy-5-fluorouridine was obtained in white,elongated, small prisms, melting at 215 The melting point did not changeafter further repeated crstallizations. The rotation was 7 2.5 $0.3".Mixtures of eand B-anomers showed melting point depressions of toAnalysis. C l-I O N F, calcd.: C, 62.3; H, 4.8; N, 5.8. Found: C, 62.61;H, 4.68; N, 5.54.

' EXAMPLE 8 a-2'De0xy-5-Flu0rouridine [VIL zzfluorinel 12 g. ofa-3',5'-di(p-toluoyl)-2-deoxy-5-luorouridine, M.P. 215", ot =72.5-J:0.3,was suspended in 130 ml. of anhydrousrnethanol. A few drops of alcoholicphenolphthalein solution were added. The suspension was cooled to 0-10and a 0.555 N barium methylate solution in methanol was added inportions, in the manner indicated in Example 6. In the present Example,10 ml. of the barium methylate solution were added initially and then,over a course of six hours, six portions of 5 ml.

each. By this time, the suspended material had practically dissolved andthe solution retained the pink color, indicating alkalinity, even uponstanding. The solution was allowed to stand in the refrigerator for 18hours longer.

Then 1 N aqueous sulfuric acid was added from a burette in an amount(22.3 ml.) equivalent to the originally added barium methylate solution.The precipitated barium sulfate was colloidal and could not be filtered.The liquid was therefore evaporated in a vacuum, the residue wasextracted twice with 50 ml. portions of boiling acetone, and the acetoneextract was filtered by suction through a filter tightened with Celite.The filtrate was evaporated in a vacuum to a syrup. The syrup was washedrepeatedly with absolute ether in order to remove methyl toluate. Theresidual syrup crystallized spontaneously after prolonged standing atroom temperature, or immediately when seeded. The crystals Were slurriedwith ether and collected by filtration. The melting point of 150-151 didnot change after recrystallization from butyl acetate. The yield (5.5g.) of u-2-deoxy-5-lluorouridine corresponded to of theory. The rotationwas -21, 2% in water. The compound gives a strong melting pointdepression with {3-2'-deoxy-5-fluorouridine.

Analysis.C l-l O N F, calcd: N, Found: N, 11.59, 11.67; F, 8.19, 8.11]

EXAMPLE 9 3 ',5-Di (p-Chlorobenzoyl) -2 -D eoxy-S-Fluorouridine [V1,Zzfluorine, Rzochlorophcnyl] 6.6 g. of mono(S-fluorouracilyDmercury wassuspended in 300 ml. of toluene in a three-neck, round-bottom flaskequipped with stirrer, -moisture-trap and reflux condenser. 'The mixturewas heated while stirring and ml. of toluene was distilled oil (bydischarging the moisture-trap when it had filled). 16.2 g. of3,5-di(p-chloro- 'benzoyl)-2-deoxy-D-ribofuranosyl chloride (V, R=p

chlorophenyl) was added. All of the material dissolved immediately.Heating was continued for 20 minutes and 50 ml. of toluene, accumulatedin the moisture-trap, was taken off. The solution was allowed to cooland then was stirred with a solution of 20 g. of potassium iodide in 80ml. of water, in order to remove mercuric chloride from the toluenelayer. The toluene layer was separated and 200 ml. of heptane was addedto it while stirring and cooling, causing precipitation of an amorphousbut filterable mixture of aand {33',5-di(p-chlorobenzoyl)-2-deoxy-S-fluorouridine. This was collected by filtration.

The reactant 3,5-di(p-chlorobenzoyl)-2-deoxy-D-ribofuranosyl chloride,referred to above, can be made by the following procedure: A

3.5 g. of dry crystalline 2deoxy-D-ribose was dissolved in 63 ml. ofmethanol and 7 ml. of a 1% solution of anhydrous hydrogen chloride inmethanol was added. The mixture was allowed to stand for 20 minutes at27. Five g. of silver carbonate was added and the mixture was stirredthoroughly. The silver salts were removed by filtration. The methanolwas distilled off in a vacuum as completely as possible, the residue wasdiluted with 10 ml. of anhydrous pyridine, and the solution was againevaporated in a vacuum in order to remove the last traces of methanol.

The oily residue, crude 1-methyl-2-deoxy-D-ribofuranoside, was dissolvedin 20 ml. of anhydrous pyridine and 8 ml. of p-chlorobenzoyl chloridewas added in portions while cooling. with ice water to maintain thetemperature between 20 and 40. The mixture was allowed to standovernight, water and methylene chloride were added, the layers wereseparated, and the methylene chloride layer was washed successively withKHSO solution and Water, dried over sodium sulfate and finallyevaporated in a vacuum.

The syrupy residue, 3,5-di(p-chlorobenzoyl)-l-methyl-2-deoxy-D-ribofuranoside, was dissolved in 20 ml. of acetic acid and 50ml. of a cold saturated solution of anhydrous hydrogen chloride in 100ml. acetic acid was added at 10-15. Crystallization of3,5-di(p-chlorobenzoyl)-deoxyribofuranosyl chloride occurred.

standing, the fi-anomer crystallized rapidly, whereas the a-anomerremained in solution. The mixture was allowed to cool and then thecrystallized precipitate was filtered by suction. The solid wasrecrystallized once from 15 to 20 ml. of acetic acid, whereupon it hadM.P. of 197-198. The yield of 3-3.5 g. correspond to 29-33% of theory.

Analysis.C H O N Cl F, calcd.: C, 52,7; H, 3.25; N, 5.35; Cl, 13.55.Found: C, 52.97; H, 3.50; CI, 13.73, 13.62.

2 g. of 18-3',5-di(p-chlorobenzoyl)2'-deoxy-5-fluorouridine wassuspended in 40 ml. of methanol and 5.5 ml. of 0.555 N methanolic bariummethylate solution was added at -5" over a period of six hours. Thematerial slowly went into solution. The mixture was allowed to stand at0-5 for 12 hours and then was worked up as described in Example 6. 0.9g. of pure ,B- 2-deoxy-5- fiuorouridine was obtained, corresponding to ayield of 88%.

EXAMPLE 12 1 -Acetylthymine [11, Z: methyl] 12.6 g. of thymine wasreacted with 50 ml. of acetic anhydride and 0.5 ml. of pyridine, insimilar manner to that described in Example 1. Upon cooling, the productcrystallized from the reaction mixture. Crystallization Was completed byadding 100 ml. of a mixture of equal volumes of ether and petroleumether. The yield of l-acetylthymine obtained was 15.2 g., correspondingto 90.5% of theory. The melting point, 197, did not change even afterrecrystallization from a large amount of ethyl acetate.

Analysis.-C H N O calcd.: C, 50.0;"H, 4.75; N, 16.7. Found: S, 51.00; H,4.53; N, 16.37, 16.21.

EXAMPLE 13 Monothyminylmercury [IV, Z=Inethy1] 16.8 g. ofl-acetylthymine was added to a hot solution of 31.8 g. of mercuricacetate in one liter of methanol, while stirring, and the mixture wasrefluxed, while stirring, for one hour. It was allowed to cool whilestirring overnight. The fine crystalline precipitate was filtered bysuction and washed on the filter with methanol. After drying at 70,monothyminylmercury was obtained as a white heavy powder, which did notmelt below 300. The yield, 32 g., was quantitative.

Analysis.-C H O N Hg, calcd.: N, 8.65. Found: N, 8.33, 8.48.

EXAMPLE 14 64 g. of monothyminylmercury was suspended in 3 liters oftoluene in a 5 liter, three-neck flask equipped with stirrer,moisture-trap, and reflux condenser. The mixture was heated whilestirring and one liter of toluene was distilled off (by discharging themoisture-trap when it had filled). The suspension was then cooled toroom temperature and 150 g. of 3,5-di(p-toluoyl)-2-deoxy-D-ribofuranosyl chloride was added. After stirring for minutes, themixture was gradually heated to the boiling point of toluene andrefluxed for minutes, with continued stirring. The mixture was allowedto cool, and then a solution of 200 g. of potassium iodide in 800 ml. ofwater was added. The mixture was stirred for several minutes in order toremove mercury from the toluene layer. The latter was then separated andevaporated in a vacuum to a syrup. The syrup was taken up in 400 ml. ofether and allowed to crystallize. The crystals of ,8-3,5-di(p-toluoyl)thymidine were collected by filtration and Y10 showed amelting point of 187-190". The yield of 48 g.

I corresponded to 50% of theory. Recrystallization from 200 ml. ofacetic acid gave 46 g. of highly pure material haw'ng M.P. 197.

EXAMPLE 15 05-3 ,5 '-Di p-Toluoyl T hymidine V1, Z=m'ethy1, R=p-to1y1]The ethereal mother liquor of the ,B-ditoluoylthymidine (Example 14) wasevaporated in vacuo, the residue was diluted with ml. of toluene, andcrude amorphous a-3',5-di(p-toluoyl)thymidine was precipitated by theaddition of 200 ml. of heptane. The gum was dissolved in as little etheras possible and was allowed'to crystallize. Crystallization oftit-3',5'-di(p-toluoyl)thymidine without seeding occurred only afterweeks, and then proceeded very slowly. Even when seeded, the solutionhad to stand for several days for completion of crystallization. Afterrecrystallization from alcohol, oc3',5'-di(ptoluoyl)thymidine melted at138. The yield amounted to 6.8 g.

EXAMPLE 16 B-Thymidine [VIL Z=methyl1 2.4 g. of,6-3',5-di(p-toluoyl)thymidine was suspended in 50 ml. of methanol and 1ml. of 0.5 N barium methylate in methanol was added. The mixture wasallowed to stand at 05 for 24 hours, with occasional shaking. To theclear solution was added 1 ml. of 0.5 N sulfuric acid, the methanol wasdistilled off in a vacuum, and the residue was washed with ether toremove methyl toluate. When seeded, the material solidified completelyto a crystalline cake of S-thymidine. To remove contaminata-Thymidine[VIL Z: methyl] Another preparation of the gummy heptane precipitate ofa-3-5-di(p-toluoyl)thymidine described in Example 15, and weighingapproximately 20 g., was dissolved in 400 ml. of methanol, and 60 ml. of0.79 N barium methylate in methanol was added. After allowing themixture to stand at room temperature for four hours, the calculatedamount of l N sulfuric acid was added. The mixture, without filtering,was then evaporated in a vacuum to a syrupy consistency, and methyltoluate was removed by washing the residue repeatedly with small amountsof ether. The residue was then taken up in '50 ml. of water and bariumsulfate was removed by filtration through a suction funnel, tightenedwith Celite, charcoal and a thin layer of freshly precipitated bariumsulfate. The filtrate was evaporated again to a syrup, and the residuewas slurried with 20 ml. of a saturated ammonium sulfate solution.a-thymidine soon crystallized. The solution was allowed to standovernight, and then the crystals were collected by filtration.Recrystallization from alcohol furnished compact well-shaped prismsmelting at 187, and showing a melting point depression with B-thymidine(melting at C.) of 10 to 15. The yield was 2.5 g.

a =+7.2i0.1, 2% in water.

Analysis.C H O N calcd.: C, 49.58; H, 5.82; N, 11.56. Found: C, 49.61;H, 5.60; N, 11.35.

EXAMPLE 1 8 a-Thymidine 2.4 g. of a-3',5'-di(p-toluoyl)thymidine of M.P.138 was suspended in 50 ml. of methanol and saponified in a mannersimilar to that indicated in Example 17, but using 0.5 N bariummethylate in methanol. The reaction mixture was worked up in a mannersimilar to Example 17. After removal of the barium as barium sulfate,and concentra tion of the filtrate, u-thymidine crystallized. It wasidentical with the produce'obtained in Example 17.

I claim: 7

1. Mono(-fiuorouracilyl)mercury.

2. A process of making mono(5-fluorouracilyl)mercury which comprisesrefluxing a lower alkanol solution ofbis(l-acetyl-S-fluorouracilyl)mercury and a mercuric salt of an organiccarhoxylic acid selectedfrom the group consisting of formic acid, aceticacid, and benzoic acid; in the proportion of 1 mol of said his compoundto at least 1 mol of said mercuric salt.

3. Bis(l-acetyl-5-fluorouracilyl}mercury.

4. A process of making mono (5-fluorouracilyl)mercury which comprisesadding l-acetyl-S-fluorouracil to a warm lower alkanol solution of amercuric salt of an organic carboxylic acidselected from the groupconsisting of formic acid, acetic acid, and benzoic acid; in theproportion of 1 mol of said l-acetyl-S-fluorouracil to more than 0.5 molof said mercuric salt.

5. A process of making mono (5-fiuorouracilyl)mercury which comprisesadding an aqueous heated solution of 5-fluorouracil to a heated loweralkanol solution of a mercuric salt of an organic carboxylic acidselected from the group consisting of formic acid, acetic acid, andbenzoic acid.

6. A process of making bis(1-acetyl-5-fiuorouracilyl) mercury whichcomprises mixing a heated alkanol solution of l-acetyl-S-fluorouracilwith a mercuric salt of an organic carboxylic' acid selected from thegroup consisting of formic acid, acetic acid, and benzoic acid in theproportion of substantially one mol to 0.5 mol.

7. A process of making monothyrninylmercury which comprises addingl-acetylthyrnine to a heated lower alkanol solution of a mercuric saltof an organic carboxylic acid selected from the group consisting offormic acid,

7 acetic acid, and benzoic acid; in the proportion of 1 mol of saidl-acetylthymine to more than 0.5 mol of said mercuric salt.

8. A process of making mono(S-fiuorouracilyDmercury which comprisesrefluxing a solution of mercuric acetate in a lower alkanol withbis(Lacetyl-S-finorouracilyl) mercury, the latter being used insubstantially equimolar proportion to the mercuric acetate.

9. A process of making mono(5-fluorouracilyl)mercury which comprisesadding l-acetyl-S-fluorouracil to a warm solution of a substantiallyequimolar proportion of mercuric acetate in a loweralkanol.

10. A process of making mono(5-fluorouracilyl)mercury which comprisesreacting S-fluorouracil with .mercuric acetate in substantiallyequimolar proportions, the reactants being in a heated aqueous loweralkanol medium.

11. A process of making monothyminylmercury which comprises addingl-acetylthymine to a hot solution of a substantially equimolarproportion of mercuric acetate in a lower alkanol.

References Cited in the file of this patent Fox et al.: J. Am, chem.Soc., vol. 78, pp. 2217-2122 (1956).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,041,335 June 26, 1962 Max Hoffer It is hereby certified that errorappears in the above numbered patent requiring correction and that thesaid Letters Patent should read as corrected below.

Column 1 lines 69 to 72, formula (IV) should appear as shown belowinstead of as in the patent:

O--l I Z I, N H

column 3, line 26, for "present" read presence column 4, llne 5, for"monothminylmercury" read monothyminylmercury line 54, f0r "4195" read41.95 column 7, line 44, for "crstallizations" read crystallizationscolumn 9, line 4, for "correspond" read corresponded line 6, for "52,7"read 52. 7 same column 9, line 37, for "S, read C, column ll line 7, for"produce" read product column 12, line 32, for "2217-2122" read Signedand sealed this 18th day of December 1962.

SEAL) \ttest:

IRNEST W. SWIDER DAVID L. LADD nesting Officer Commissioner of Patents

1. MONO(5-FLUOROURACILYL) MERCURY.